GTN is an active substance which is used in the treatment of attacks of angina pectoris, among other uses, whereby it is especially used in emergency situations, in which the pharmaceutical form must enable a rapid onset of action. Within this framework sublingual administration has proven very effective with rapid uptake of the active substance and quick relief of symptoms. In addition to sublingual sprays, solutions for infusion or chewable capsules, tablets for oromucosal, i.e. sublingual or buccal administration are used as pharmaceutical forms to enable rapid onset of action.
Sprays for sublingual administration, which are used to spray the active substance-containing dose underneath the tongue, provide for a direct and rapid application of the dissolved active substance over the highly resorbent oral mucosa. However, affected patients are required to carry a relatively voluminous spray bottle around with them at all times in order to ensure immediate access to the medicinal product in emergencies and enable a rapid administration of the GTN. Alternatively, chewable capsules containing the active substance as an oily solution can be carried around as individual doses in blisters. However, a portion of the active ingredient, which is released by tearing open the capsules with the teeth, never reaches the sublingual area, its absorption is delayed or it is lost through swallowing. Sublingual tablets represent a further alternative to spray solutions and chewable capsules because they can be placed directly under the tongue to rapidly release the active substance. However, these, too, have many disadvantages which are well known.
GTN is not a stable substance. It is explosive as a pure substance and is used as an explosive in the form of dynamite. In addition, GTN is volatile even when prepared as a solid commercially available medicinal product. Phlegmatized solutions with ethanol, propylene glycol or medium chain triglycerides, for example, are less reactive and permit the safe preparation of GTN concentrates in liquid form. As a triple ester, GTN is readily hydrolyzed both in the acidic and alkaline pH range. Degradation reactions form 1,3- or 1,2-glyceryl dinitrate (GDN) and 1- or 2-glyceryl mononitrate (GMN), which limits the storage stability and shelf life of GTN formulations.
Up to now commercially available GTN tablets have been filled in glass bottles, which must be handled with a certain level of caution when carried around by patients. In addition, the removal of a single tablet can be difficult in an emergency situation, due to the small size of the tablets, among other reasons. Thus, there is a long felt unmet need for alternative forms of GTN-containing solid compounds, which are easy for patients to carry around in single-dose form, e.g. in a wallet or jacket pocket, and which simultaneously ensure sufficient stability, simple administration, and rapid onset of action.
So-called stick packs represent an alternative pharmaceutical configuration for individual doses. They can be manufactured to contain the medicinal product as free-flowing granules or powder and enable both comfortable transport of the medicinal product as well as simple and easy dosing, which is especially significant in emergency situations. However, GTN-containing powders or granules—with their substantially larger total surface area as compared with tablets—represent an even greater challenge with respect to stabilization of the composition in any type of packaging configuration including stick packs. In the case of GTN, the highest possible storage stability is especially critical to enable the patient to carry around a single dose such as but not limited to a stick pack; carrying it around in the breast pocket of a shirt, for example, can subject it to significant temperature increases and associated stress conditions, which may violate the recommended storage conditions for conventional GTN compounds.
Thus, one object of the present invention is to provide a highly stable, solid pharmaceutical preparation containing GTN, which is suitable for oromucosal administration and can be used in the production of a pharmaceutical form such as a powder, granule or tablet, which patients can carry around comfortably in an easy-to-use, unbreakable single-dose configuration such as but not limited to single doses in a stick pack. Another object of the present invention is to provide a method of production to ensure safe and reliable manufacturing on an industrial scale of a highly stabilized GTN-containing preparation and consumer medicine.